Microcapsules and Microspheres formed from various natural and synthetic polymers and resins have become popular delivery vehicles for various active agents such as drugs, diagnostic reagents and the like. Degradable microcapsules and microspheres are of particular interest for use in so called "depot" formulations, where delivery of the active agent over an extended period of time is desired. Despite the growing number of uses of microcapsules and microspheres, there remains a need for an economic and reliable method for their manufacture that avoids the most significant wastes and expenses associated with existing methods, while simultaneously providing products having the most desirable properties.
Processes for preparing microspheres typically involve the formation of at least one dispersed phase in a continuous phase. The dispersed phase typically includes the active agent and polymer and, upon solidification in the continuous phase, becomes a microsphere. Microcapsules are similarly formed using multiple phases. In a typical practice, a water-oil-water (w/o/w) emulsion is formed, and the polymer caused to precipitate out of one phase onto the surface of a dispersed phase to form a capsule wall thereon upon solidification of the polymer.
One difficulty with current processes is their inability to efficiently produce small particles that exhibit all of the desired properties of drug incorporation, low residual solvent and scalability. When microspheres are intended for subcutaneous, intramuscular or intravenous delivery, small particles are required. However, obtaining small particles typically requires a continuous phase having a high surfactant concentration and/or viscosity of the continuous phase, and/or a low viscosity dispersed phase. This can necessitate adjusting the viscosity and increases the energy input needed for small particles, thereby further complicating the process. Moreover, it is often necessary to use a highly viscous dispersed phase in order to obtain higher drug loads. However, it is extremely difficult to obtain small particles with a highly viscous dispersed phase. Moreover, the stirring required to obtain the desired particle sizes frequently results in excessive foaming, especially when increased surfactant concentrations or lower viscosity continuous phases are used. This is problematic in many systems because, while cooling the system will increase the viscosity and help to stabilize the droplets and reduce foaming, the viscosity of the DP will tend to increase more dramatically than, for example, a typically aqueous continuous phase. This will make it more difficult to obtain small droplets. Still further, if the concentration of the drug is close to the solubility limit of the dispersed phase solution, the drug could crystalize out of the system, which can result in low drug incorporation and burst problems in the release profile.
In many cases, foaming will make it impossible to obtain the desired particle size. In other cases, the dispersed phase droplets will escape the mixing zone and will result in larger particles and an unacceptable particle size distribution. In still other cases, a suitable particle size might be achieved, but drug load is inefficient, which can render the process commercially unviable.
Another problem encountered with existing processes occurs in scale up. Once one obtains a batch of microspheres or microcapsules having the desired characteristics, such as particle size, drug load, release profile and the like, it is then necessary to scale up the process for commercial production. Scaling up to commercial production typically involves several successively larger production runs, with various process parameters changing with each successive scale up. A great deal of experimentation can be necessary to finally obtain a commercial scale batch having the characteristics of the initial run. When a single gram of some of today's more exotic drugs can cost many thousands of dollars, having to experiment at each successive level of scale up can be extremely expensive. Likewise, the time and capital expense associated with the scale up of such processes can put one at a significant competitive disadvantage.
There is a need for a process that can efficiently produce small particle sizes with good drug loading in a continuous manner. The process must be easily adapted to a wide variety of active agents and polymers, enable economic and efficient scale up to commercial production and produce uniform products throughout a given production run.